Search

A 71-year-old man visited our hospital with dyspnea and left pleural effusion. Left pleural effusion was diagnosed as chylothorax by thoracentesis. He had no history of trauma or surgery, and there were no findings of malignant lymphoma or thrombosis. Furthermore, he was diagnosed with liver cirrhosis and hepatocellular carcinoma by computed tomography and hematological examinations, and the chylothorax was considered to be caused by liver cirrhosis. We report a review of the literature with this case since it is relatively rare for cirrhosis and hepatocellular carcinoma diagnosed from chylothorax.

We postulated that disinfection of viable Trichophyton species in shoes would help reduce the number of patients with tinea pedis in Japan and that this might be accomplished safely using volatile components of essential oils. As vapor of lemongrass (Cymbopogon citratus) oil and citral have strong antimicrobial activities against Trichophyton, we examined the conditions under which lemongrass oil or citral show optimal antimicrobial activity in shoes. First, we investigated whether or not a strong antimicrobial effect could be obtained by combining with terpene aldehydes or aromatic aldehydes. When combined with citral, perillaldehyde showed superior antimicrobial activity to citronellal, cinnamaldehyde, cuminaldehyde, hydroxycitronellal, and vanillin. The combined effects of citral and perillaldehyde against Trichophyton mentagrophytes, Bacillus subtilis, and Candida albicans as volatile components dotted on filter paper placed away from the petri dish inoculated with fungi or bacteria were examined. Citral (2.5 mg/mL) and perillaldehyde (2.5 mg/mL) showed a greater inhibitory effect on growth of C. albicans than either solution alone in the aromatogram (disc diffusion) descent method (fractional inhibitory concentration [FIC] index of 0.58). Citral (2.5 mg/mL) and perillaldehyde (1.25 mg/mL) vapors in a closed box synergistically inhibited growth of B. subtilis and T. mentagrophytes (FIC indexes of 0.5 and 0.38, respectively). These results suggested that this combination would be safe and useful for disinfection of shoes.

A 56-year-old man with severe asthma underwent bronchial thermoplasty (BT). However, his asthma exacerbated and hypereosinophilia developed 2 months later, thus necessitating oral corticosteroid (OCS) therapy. Six months after BT, a diagnosis of severe asthma with eosinophilic chronic rhinosinusitis (ECRS) was made and benralizumab treatment was initiated; the blood eosinophil count subsequently decreased and lung function improved, thereby permitting OCS dose tapering. Surprisingly, benralizumab both reduced nasal polyps and ameliorated ECRS. Thus, benralizumab may be a useful drug for the rapid treatment of severe asthma with ECRS, especially in patients with hypereosinophilia., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Objective: We aimed to investigate factors predictive of increased serum infliximab (IFX) concentration with improvement of disease activity, as well as better 1-year continuation rate after dose escalation, in patients with rheumatoid arthritis (RA) who showed inadequate response to 3 mg/kg IFX., Methods: Among 42 patients allotted to receive 3 mg/kg IFX, 13 patients showed adequate response (DAS28 < 3.2) and 29 patients required dose escalation to 4.5 or 6 mg/kg after inadequate response (DAS28 ≥ 3.2) to 3 mg/kg IFX. DAS28, mHAQ, serum level of CRP, interleukin (IL)-6, IL-17, anti-infliximab antibody (AIA) titers and IFX concentration before and on average 2.7 months after dose escalation were examined to explore the baseline factors predictive of a clinically beneficial increase of serum IFX concentration and drug survival., Results: One year after IFX dose escalation, 25 patients completed the study protocol, and 16 patients (64%) continued to show a good response for one year, while 9 patients (36%) required switching of biologics because of inadequate response. Multivariate analyses revealed that a serum IL-6 level of less than 4.0 pg/mL at baseline was the only factor predictive of a clinically beneficial increase of serum IFX concentration in patients who required dose escalation. Receiver operating characteristic analysis revealed that 5.16 pg/mL of IL-6 was the cut-off value with sensitivity 0.833 and specificity of 0.769 (95%CI for AUC: 0.712-1.006). In patients with IL-6 levels of less than 5.16 pg/mL at baseline, the serum IFX concentration significantly increased after dose escalation with adequate response. The 1-year drug survival rates of patients with IL-6 levels less than 5.16 pg/mL and in those with levels greater than or equal to 5.16 pg/mL at baseline were 83.3% and 30.8%, respectively (log-rank test, p = .011)., Conclusions: The results of our study indicated that a baseline serum level of IL-6 below 5.16 pg/mL might be a predictive factor for a clinically beneficial increase of serum IFX concentration with improvement of disease activity and better 1-year continuation rate after IFX dose escalation.

Aim: To describe medication use including potentially inappropriate medication (PIM) and examine the association between adverse outcomes and patient factors including PIM use in Japanese elderly patients in long-term care facilities., Methods: This was a retrospective cohort study of 470 patients in 53 Geriatric Health Service Facilities and 44 Sanatorium Type Medical Care Facilities for the Elderly Requiring Long Term Care. Standardized forms were used to collect information including oral and parenteral medication use on admission, and 1 month and 3 months after admission. PIMs were determined by the 2003 or 2012 Beers criteria. Adverse outcomes were any medical events leading to emergency department transfer, hospitalization to acute care hospitals or death., Results: A total of 2,227 oral medications and 197 parenteral medications were prescribed for 470 patients on admission. PIM exposure based on the 2003 and 2012 Beers criteria was observed in 11.9% and 37.5%, respectively. Adverse outcomes within 3 months after admission were observed in 8.9% of the entire cohort, and were associated with age, sex, facility type and number of parenteral medications on admission. Adverse outcomes between one and three months after admission were associated with age, sex, number of parenteral medications at one month, and a change in the number of oral and parenteral medications within one month after admission. PIM exposure was not associated with adverse outcomes in any models., Conclusions: Use of PIM was prevalent in long-term care facilities. Our findings support the importance of comprehensive assessment of medication regimens including parenteral medication. Geriatr Gerontol Int 2017; 17: 591-597., (© 2016 Japan Geriatrics Society.)

Background: Insertions and deletions (indels) account for more nucleotide differences between two related DNA sequences than substitutions do, and thus it is imperative to develop a method to reliably calculate the occurrence probabilities of sequence alignments via evolutionary processes on an entire sequence. Previously, we presented a perturbative formulation that facilitates the ab initio calculation of alignment probabilities under a continuous-time Markov model, which describes the stochastic evolution of an entire sequence via indels with quite general rate parameters. And we demonstrated that, under some conditions, the ab initio probability of an alignment can be factorized into the product of an overall factor and contributions from regions (or local alignments) delimited by gapless columns., Results: Here, using our formulation, we attempt to approximately calculate the probabilities of local alignments under space-homogeneous cases. First, for each of all types of local pairwise alignments (PWAs) and some typical types of local multiple sequence alignments (MSAs), we numerically computed the total contribution from all parsimonious indel histories and that from all next-parsimonious histories, and compared them. Second, for some common types of local PWAs, we derived two integral equation systems that can be numerically solved to give practically exact solutions. We compared the total parsimonious contribution with the practically exact solution for each such local PWA. Third, we developed an algorithm that calculates the first-approximate MSA probability by multiplying total parsimonious contributions from all local MSAs. Then we compared the first-approximate probability of each local MSA with its absolute frequency in the MSAs created via a genuine sequence evolution simulator, Dawg. In all these analyses, the total parsimonious contributions approximated the multiplication factors fairly well, as long as gap sizes and branch lengths are at most moderate. Examination of the accuracy of another indel probabilistic model in the light of our formulation indicated some modifications necessary for the model's accuracy improvement., Conclusions: At least under moderate conditions, the approximate methods can quite accurately calculate ab initio alignment probabilities under biologically more realistic models than before. Thus, our formulation will provide other indel probabilistic models with a sound reference point.

Background: Insertions and deletions (indels) account for more nucleotide differences between two related DNA sequences than substitutions do, and thus it is imperative to develop a stochastic evolutionary model that enables us to reliably calculate the probability of the sequence evolution through indel processes. Recently, indel probabilistic models are mostly based on either hidden Markov models (HMMs) or transducer theories, both of which give the indel component of the probability of a given sequence alignment as a product of either probabilities of column-to-column transitions or block-wise contributions along the alignment. However, it is not a priori clear how these models are related with any genuine stochastic evolutionary model, which describes the stochastic evolution of an entire sequence along the time-axis. Moreover, currently none of these models can fully accommodate biologically realistic features, such as overlapping indels, power-law indel-length distributions, and indel rate variation across regions., Results: Here, we theoretically dissect the ab initio calculation of the probability of a given sequence alignment under a genuine stochastic evolutionary model, more specifically, a general continuous-time Markov model of the evolution of an entire sequence via insertions and deletions. Our model is a simple extension of the general "substitution/insertion/deletion (SID) model". Using the operator representation of indels and the technique of time-dependent perturbation theory, we express the ab initio probability as a summation over all alignment-consistent indel histories. Exploiting the equivalence relations between different indel histories, we find a "sufficient and nearly necessary" set of conditions under which the probability can be factorized into the product of an overall factor and the contributions from regions separated by gapless columns of the alignment, thus providing a sort of generalized HMM. The conditions distinguish evolutionary models with factorable alignment probabilities from those without ones. The former category includes the "long indel" model (a space-homogeneous SID model) and the model used by Dawg, a genuine sequence evolution simulator., Conclusions: With intuitive clarity and mathematical preciseness, our theoretical formulation will help further advance the ab initio calculation of alignment probabilities under biologically realistic models of sequence evolution via indels.

Background: Reconstruction of multiple sequence alignments (MSAs) is a crucial step in most homology-based sequence analyses, which constitute an integral part of computational biology. To improve the accuracy of this crucial step, it is essential to better characterize errors that state-of-the-art aligners typically make. For this purpose, we here introduce two tools: the complete-likelihood score and the position-shift map., Results: The logarithm of the total probability of a MSA under a stochastic model of sequence evolution along a time axis via substitutions, insertions and deletions (called the "complete-likelihood score" here) can serve as an ideal score of the MSA. A position-shift map, which maps the difference in each residue's position between two MSAs onto one of them, can clearly visualize where and how MSA errors occurred and help disentangle composite errors. To characterize MSA errors using these tools, we constructed three sets of simulated MSAs of selectively neutral mammalian DNA sequences, with small, moderate and large divergences, under a stochastic evolutionary model with an empirically common power-law insertion/deletion length distribution. Then, we reconstructed MSAs using MAFFT and Prank as representative state-of-the-art single-optimum-search aligners. About 40-99% of the hundreds of thousands of gapped segments were involved in alignment errors. In a substantial fraction, from about 1/4 to over 3/4, of erroneously reconstructed segments, reconstructed MSAs by each aligner showed complete-likelihood scores not lower than those of the true MSAs. Out of the remaining errors, a majority by an iterative option of MAFFT showed discrepancies between the aligner-specific score and the complete-likelihood score, and a majority by Prank seemed due to inadequate exploration of the MSA space. Analyses by position-shift maps indicated that true MSAs are in considerable neighborhoods of reconstructed MSAs in about 80-99% of the erroneous segments for small and moderate divergences, but in only a minority for large divergences., Conclusions: The results of this study suggest that measures to further improve the accuracy of reconstructed MSAs would substantially differ depending on the types of aligners. They also re-emphasize the importance of obtaining a probability distribution of fairly likely MSAs, instead of just searching for a single optimum MSA.

Introduction: Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA., Method: We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed., Results: Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10(-8)), followed by rs6986423 in CSMD1 (p = 2.4 × 10(-6)) and rs17727339 in FCRL3 (p = 1.4 × 10(-5)). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations., Conclusion: Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

Introduction: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice., Methods: This prospective cohort study included RA patients starting TCZ [TCZ group, n=302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n=304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis., Results: Patients in the TCZ group had longer disease duration (P<0.001), higher disease activity (P=0.019) and more frequently used concomitant corticosteroids (P<0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37)., Conclusions: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

In a preceding paper, we showed that aroma candy containing oligonol, capric acid, and cinnamon (cassia) powder had potent inhibitory activity against mycelial growth of Candida albicans in vitro and protective activity against murine oral candidiasis. In order to assess the effects of this candy (the test candy) on oral C. albicans colony-forming units (CFU) and oral hygiene states, a placebo-controlled double-blind crossover comparative study was performed. Twenty subjects were divided into two groups. One group ingested the test candy in the first 7 days followed by 2 weeks washing-off period, then ingested the placebo candy (control candy) for 7 days. The other group was vice versa. C. albicans CFU in all oral rinse samples from the subjects before and after 7 days ingestion of candy was measured. The degree of oral malodor in all subjects was monitored using a portable measuring instrument. The results showed no statistically significant difference between test-candy group and placebo group for C. albicans CFU. However, C. albicans CFU in test-candy group with>4,000 CFUs was significantly decreased after 7 days ingestion of test-candy (p<0.05). Scores of oral malodor in the test-candy group was significantly decreased after 7 days ingestion of test-candy (p<0.05). A questionnaire survey of oral hygiene states indicated that in the test-candy group, oral malodor, glutinous feeling, and refreshing feeling significantly improved in comparison with control-candy group (p<0.05). Our study suggests that the aroma candy is effective in oral health care of elderly carrying C. albicans.

A daily eatable candy that has possible protective activity against oral candidiasis was experimentally produced. The candy was made from reduced-maltose as main constituent and from several natural products, such as oligonol (depolymerized polyphenols derived from lychee), cinnamon (cassia), citral, and capric acid, which are known to have anti-Candida activity in vitro and in vivo. The candy effectively inhibited the mycelial growth of C. albicans, even when it was diluted 1,000 times with culture media. We assessed the protective activity of the candy against murine candidiasis. When 50μl of candy dissolved and diluted 4 times with water was administered 3 times into the oral cavity of Candida infected mice, the score of lesions on the Candida-infected tongues improved on day 2. These findings suggest that this candy has potential as food that provides protective activity against oral candidiasis.

Objective: To compare the incidence and risk factors of serious adverse events (SAEs) in rheumatoid arthritis (RA) patients treated with etanercept (ETN) or adalimumab (ADA) between Korean and Japanese registries., Methods: We recruited 416 RA patients [505.2 patient-years (PYs)] who started ETN or ADA from Korean registry and 537 RA patients (762.0 PY) from Japanese registry. The patient background, incidence rate (IR) of SAE in 2 years, and risk factors for SAEs were compared., Results: Korean patients were younger and used more nonbiologic DMARDs, higher doses of methotrexate, and lower doses of prednisolone (PSL). The IR of SAEs (/100 PY) was higher in the Japanese registry compared to the Korean [13.65 vs. 6.73]. In both registries, infection was the most frequently reported SAE. The only significant risk factor for SAEs in Korean registry was age by decade [1.45]. In Japanese registry, age by decade [1.54], previous use of nonbiologic DMARDs ≥ 4 [1.93], and concomitant use of oral PSL ≥ 5 mg/day [2.20] were identified as risk factors for SAEs., Conclusions: The IR of SAE in Japan, especially infection, was higher than that of Korea, which was attributed to the difference of demographic and clinical characteristics of RA patients and treatment profiles.

Purpose: We explored a recovery correction technique that can correct metabolite loss during perchloric acid (PCA) extraction and minimize inter-assay variance in quantitative (1)H nuclear magnetic resonance (NMR) spectroscopy of the brain and evaluated its efficacy in 5-fluorouracil (5-FU)- and saline-administered rats., Methods: We measured the recovery of creatine and dl-valine-2,3-d2 from PCA extract containing both compounds (0.5 to 8 mM). We intravenously administered either 5-FU for 4 days (total, 100 mg/kg body weight) or saline into 2 groups of 11 rats each. We subsequently performed PCA extraction of the whole brain on Day 9, externally adding 7 µmol of dl-valine-2,3-d2. We estimated metabolite concentrations using an NMR spectrometer with recovery correction, correcting metabolite concentrations based on the recovery factor of dl-valine-2,3-d2. For each metabolite concentration, we calculated the coefficient of variation (CEV) and compared differences between the 2 groups using unpaired t-test., Results: Equivalent recoveries of dl-valine-2,3-d2 (89.4 ± 3.9%) and creatine (89.7 ± 3.9%) in the PCA extract of the mixed solution indicated the suitability of dl-valine-2,3-d2 as an internal reference. In the rat study, recovery of dl-valine-2,3-d2 was 90.6 ± 9.2%. Nine major metabolite concentrations adjusted by recovery of dl-valine-2,3-d2 in saline-administered rats were comparable to data in the literature. CEVs of these metabolites were reduced from 10 to 17% before to 7 to 16% after correction. The significance of differences in alanine and taurine between the 5-FU- and saline-administered groups was determined only after recovery correction (0.75 ± 0.12 versus 0.86 ± 0.07 for alanine; 5.17 ± 0.59 versus 5.66 ± 0.42 for taurine [µmol/g brain tissue]; P < 0.05)., Conclusion: A new recovery correction technique corrected metabolite loss during PCA extraction, minimized inter-assay variance in quantitative (1)H NMR spectroscopy of brain tissue, and effectively detected inter-group differences in concentrations of brain metabolites between 5-FU- and saline-administered rats.

Objectives: Physicians are uncertain about what medical services should be provided to older and/or disabled patients. Better understanding of health outcome prioritization among health care providers and recipients may help the process of decision- and policy-making. For this purpose, surveys were conducted on priorities of health care outcomes for the elderly., Design: Survey research., Setting: Four groups of health care providers and four groups of health care recipients., Participants: A total of 2512 health care providers and 4277 recipients., Measurements: Questionnaires were sent to more than 8000 health care providers and more than 9000 health care recipients: geriatricians, physicians who commonly see older patients or work in long term care facilities, staff members and participants in adult day care, patients in outpatient geriatric clinics, family members of patients with dementia, and community-dwelling older adults. The questionnaire asked the subjects to rank 12 measures of health care outcomes., Results: The mean response rate was 49%. All health care provider groups considered "improvement of quality of life" the most important. In contrast, in health care recipient groups, "effective treatment of illness," "improvement of physical function," and "reduction of carer burden" were given high priority, whereas "improvement of quality of life" was perceived as less important. All the groups, including health care providers and recipients, ranked "reduction of mortality" the least important, followed by "avoiding institutional care." Stratification analysis showed that the results did not differ by sex, nursing care level, or the existence of relatives who required nursing care, whereas age slightly influenced the order of high-ranked measures., Conclusion: Priorities of health care services and their differences between providers and recipients should be taken into account in the health care of older patients and the design of health care policies and research., (Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To explore simultaneous magnetic resonance imaging (MRI) for multiple hepatoma-bearing rats in a single session suppressing motion- and flow-related artifacts to conduct preclinical cancer research efficiently., Materials and Methods: Our institutional Animal Experimental Committee approved this study. We acquired PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) T2 - and diffusion-weighted images of the liver in one healthy and 11 N1-S1 hepatoma-bearing rats in three sessions using a 3-T clinical scanner and dedicated multiarray coil. We compared tumor volumes on MR images and those on specimens, evaluated apparent diffusion coefficients (ADC) of the tumor, and compared them to previously reported values., Results: Each MRI session took 39-50 minutes from anesthesia induction to the end of scans for four rats (10-13 minutes per rat). PROPELLER provided artifact-reduced T2 - and diffusion-weighted images of the rat livers. Tumor volumes on MR images ranged from 0.04-1.81 cm(3) and were highly correlated with those on specimens. The ADC was 1.57 ± 0.37 × 10(-3) mm(2) /s (average ± SD), comparable to previously reported values., Conclusion: PROPELLER allowed simultaneous acquisition of artifact-reduced T2 - and diffusion-weighted images of multiple hepatoma-bearing rats. This technique can promote high-throughput preclinical MR research for liver cancer., (Copyright © 2013 Wiley Periodicals, Inc.)

The population genetic behavior of mutations in sperm genes is theoretically investigated. We modeled the processes at two levels. One is the standard population genetic process, in which the population allele frequencies change generation by generation, depending on the difference in selective advantages. The other is the sperm competition during each genetic transmission from one generation to the next generation. For the sperm competition process, we formulate the situation where a huge number of sperm with alleles A and B, produced by a single heterozygous male, compete to fertilize a single egg. This "minimal model" demonstrates that a very slight difference in sperm performance amounts to quite a large difference between the alleles' winning probabilities. By incorporating this effect of paternity-sharing sperm competition into the standard population genetic process, we show that fierce sperm competition can enhance the fixation probability of a mutation with a very small phenotypic effect at the single-sperm level, suggesting a contribution of sperm competition to rapid amino acid substitutions in haploid-expressed sperm genes. Considering recent genome-wide demonstrations that a substantial fraction of the mammalian sperm genes are haploid expressed, our model could provide a potential explanation of rapid evolution of sperm genes with a wide variety of functions (as long as they are expressed in the haploid phase). Another advantage of our model is that it is applicable to a wide range of species, irrespective of whether the species is externally fertilizing, polygamous, or monogamous. The theoretical result was applied to mammalian data to estimate the selection intensity on nonsynonymous mutations in sperm genes.

Background: Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such "recurrent mutations" might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence., Results: Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary., Conclusions: With their considerably high powers to detect negative selection, our new neutrality tests may open new venues for dealing with the population genetics of recurrent mutations as well as help identifying some types of genetic disorders that may have escaped identification by currently existing methods.

Duplogs, or intraspecies paralogs, constitute the important portion of eukaryote genomes and serve as a major source of functional innovation. We conducted detailed analyses of recently emerged animal duplogs. Genome data of three vertebrate species (Homo sapiens, Mus musculus, and Danio rerio), Caenorhabditis elegans, and two Drosophila species (Drosophila melanogaster and D. pseudoobscura) were used. Duplication events were divided into six age-groups according to the synonymous distance (dS) up to 0.6. Duplogs were classified into four equal-sized classes on physical distances and into three classes on relative orientations. We observed the following shared characteristics among intrachromosomal multiexon duplogs: 1) inverted duplogs account for 20-50%, and about a half of the physically most distant 25%; 2) except for C. elegans, the composition of physical distances, that of relative orientations, and the proportion of inverted duplogs in each physical distance category are more or less uniform; 3) except for C. elegans, the characteristics of the youngest (dS < 0.01) duplogs are similar to the overall characteristics of the entire set. These results suggest that intrachromosomal duplogs with fairly long physical distances were generated at once, rather than resulting from tandem duplications and subsequent genomic rearrangements. This is different from the three well-known modes of gene duplication: tandem duplication, retrotransposition, and genome duplication. We termed this new mode as "drift" duplication. The drift duplication has been producing duplicate copies at paces comparable with tandem duplications since the common ancestor of vertebrates, and it may have already operated in the common ancestor of bilateral animals.

We developed two new radiographic parameters-the humeral surface height ratio and ulnar surface height ratio-to precisely detect changes in the bony structure of rheumatoid elbows. Of the 59 patients with rheumatoid arthritis, 101 elbows were classified into four types (osteoarthritis, ankylosis, erosive, and resorptive) according to the radiographic appearance. Clinically, osteoarthritis type and ankylosis type were considered to be stable form, and erosive type and resorptive type were unstable form. Patients' clinical data and yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and ulnar surface height ratio were compared among the four types and between the two forms. There were significant differences between the two forms and among the three types except for the ankylosis type in yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and ulnar surface height ratio. Stable and unstable forms were distinguished by a cut-off point of 0.65 and 2.58 in yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and the ulnar surface height ratio, respectively. These parameters might be useful for monitoring the structural changes of the elbow joint in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive joint destruction that requires aggressive treatment using appropriate disease-modifying antirheumatic drugs (DMARDs). RA patients with renal failure, however, are intolerant to most DMARDs due to the potential toxicity. In Japan, tacrolimus was approved for the treatment of RA in 2005. Based on its pharmacokinetics, tacrolimus may be administered to the patients undergoing hemodialysis. We report two cases of RA patients on hemodialysis treated effectively and safely with tacrolimus.